PRECLINICAL GVHD AND MARROW ENGRAFTMENT STUDIES

（申请人描述）移植物抗宿主病（GvHD）是同种异体骨髓移植（BMT）的主要并发症。骨髓供体和受体的hla匹配可以降低GvHD的风险，匹配的兄弟姐妹是首选。然而，只有大约30%的患者有hla匹配的兄弟姐妹，因此必须通过国家骨髓捐赠计划（NMDP）寻找合适的非亲属hla匹配的捐赠者。在不相关的hla匹配患者中，GvHD的风险仍然很高，特别是由于MHC II类位点的遗传变异，其产物可以诱导CD4+ T细胞反应。骨髓移植排斥反应的预防也是同种异体骨髓移植的一个关键问题，特别是当涉及MHC II类错配时。作为该项目的一部分，我们专注于结构基设计的抑制CD4+ T细胞介导的同种异体反应性的肽和有机化合物的临床前研究。我们将集中精力开发三组抑制剂：(1)D1 CC环肽（802-2），目前临床试验的先导化合物；(2)设计用于抑制CD4分子D4结构域二聚化的新肽；(3)选择两种有机化合物（TJU103和TJU104），因为它们能够阻断D1结构域上假定的结合口袋。我们将使用的BMT模型包括：(1)MHC单倍体相同的B6D2->B6CB （950 cGy）和次要组织相容性抗原(HA)-错配的B6 ->BALB。GvHD的B （850 cGy）模型；2) MHC单倍体相同的B6CB ATBM->B6D2 (750 cGy)， MHC ii类异位的Bm12 ATBM->B6.Ly5.2 (700 cGy)，以及cd4 - ii类限制性的次要ha -异位BALB。B ATBM->B6 （700 cGy）呈现同种异体骨髓移植排斥反应模型。通过在这些模型中选择的肽和化合物，我们的具体目标是：1)确定802-2，CD4 D4和有机抑制剂在GvHD和骨髓移植排斥模型中的功效；(2)确定抑菌剂的作用机制；(3)评价GvHD模型BMT受体在抑制剂治疗后的免疫功能状态。这些研究将为这些新的CD4抑制剂提供强有力的临床前基础，这些抑制剂可能潜在地靶向同种异体反应细胞，而不会损害后来对感染和白血病的免疫反应。

DESCRIPTION: (Applicant's Description) Graft-versus-host disease (GvHD) is a major complication of allogeneic bone marrow transplantation (BMT). The risk of GvHD can be reduced by HLA-matching of the marrow donor and recipient, with a matched sibling being the primary choice. Yet, only about 30% of patients have a HLA-matched sibling, and thus must seek suitable unrelated HLA-matched donors through the National Marrow Donor Program (NMDP). The risk of GvHD is still quite high in unrelated HLA-matched patients, particularly due to genetic variants in MHC class II loci, whose products can induce CD4+ T cell responses. The prevention of marrow graft rejection is also a critical issue for allogeneic BMT, particularly when involving MHC class II mismatches. As part of this Program, we have focused our attention on the preclinical investigation of structure-base designed peptides and organic compounds that inhibit CD4+ T cell-mediated alloreactivity. We will concentrate our efforts on three groups of inhibitors: (1) the D1 CC' loop peptide (802-2), the lead compound for the current clinical trial; (2) new peptides designed to inhibit dimerization of CD4 molecules in the D4 domain; and (3) two organic compounds (TJU103, and TJU104) that were selected for their ability to block a putative binding pocket on the D1 domain. The BMT models that we will utilize include: (1) the MHC haploidentical B6D2->B6CB (950 cGy) and minor histocompatibility antigen (HA)-mismatched B6 ->BALB.B (850 cGy) models of GvHD; and 2) the MHC haploidentical B6CB ATBM->B6D2 (750 cGy), MHC Class II-disparate Bm12 ATBM->B6.Ly5.2 (700 cGy), and the CD4-Class II-restricted minor HA-disparate BALB.B ATBM->B6 (700 cGy) presensitized models of allogeneic marrow graft rejection. With the selected peptides and compounds in these models, our specific aims are: 1) to determine the efficacy of the 802-2, CD4 D4, and organic inhibitory agents in the GvHD and marrow graft rejection models; (2) to determine mechanism of action of the inhibitory agents; and (3) to evaluate the immunocompetent status of BMT recipients in the GvHD models after treatment with the inhibitory agents. These studies will provide a strong preclinical basis for these novel CD4 inhibitors that could potentially target alloreactive cells without jeopardizing later immune responses to infection and leukemia.